1. Field of the Invention
This invention relates to a process for the synthesis of a natural peptide having medicinal uses. In particular, this invention concerns a process for the preparation of L-carnosine, beta-alanyl-L-histidine.
2. Description of the Art
L-Carnosine, beta-alanyl-L-histidine, is a natural occurring dipeptide which is found in vertebrate skeletal muscle and in the olfactory bulbs and nasal tissue of animals. Recently it has been shown in a review by K. Nagai and T. Yamane [Heterocycles, 10, 277 (1978)] that L-carnosine possesses the remarkable property of accelerating wound healing particularly when used following oral surgical procedures [K. Nagai, et al., J. Nihon Univ. Sch. Dent., 16, 29 (1974)].
L-Carnosine has been synthesized by (1) the reaction of L-histidine with beta-iodopropionyl chloride followed by treatment with ammonia [L. Baumann, et al., J. Biol. Chem., 35, 263 (1918)]; (2) reaction of beta-carbobenzoxypropionyl azide with L-histidine methyl ester followed by ester hydrolysis and deblocking [R. Sifferd, et al., J. Biol. Chem., 108, 753 (1935)]; (3) reaction of beta-phthaloylalanyl chloride with L-histidine followed by removal of the phthaloyl group [R. Turner, J. Am. Chem. Soc., 75, 2388 (1953) and G. Losse, et al., Chem. Ber. 94, 2768 (1961)]; (4) reaction of L-histidine and a mixed anhydride of beta-phthaloylalanyl followed by removal of the phthaloyl group [H. Rinderknecht, et al., J. Org. Chem., 229, 1968 (1964)]; (5) acylation of L-histidine methyl ester with beta-phthaloylalanine p-nitrophenyl ester followed by removal of the phthaloyl group [A. A. Glemzha, et al., Izo. Akad. Nauk. USSR, Ser. Khim, 861 (1966)]; and (6) reaction of carbobenzoxybeta-alanine p-nitrophenyl ester with L-histidine followed by removal of the blocking group [C. Pinelli, et al., Il Farmico, Ed. Sci., 23, 859 (1968)].
Recently, U.S. Pat. No. 3,846,398 reported the synthesis of peptides of alpha-amino acids using a substituted thiazolid-2,5-dione, in which the pH control was adjusted with inorganic acids and an alkali metal hydroxide.